中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (4): 887-897.doi: 10.4103/1673-5374.322475

• 原著:退行性病与再生 • 上一篇    下一篇

下调HOTTIP可减轻缓解帕金森病神经元损伤和小胶质细胞活化

  

  • 出版日期:2022-04-15 发布日期:2021-10-18

HOTTIP downregulation reduces neuronal damage and microglial activation in Parkinson’s disease cell and mouse models

Peng Lun1, #, Tao Ji2, #, De-Hong Wan1, Xia Liu3, Xiao-Dong Chen4, Shuai Yu4, Peng Sun1, *   

  1. 1Department of Neurosurgery, the Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China; 2Department of Neurosurgery, Laiyang People’s Hospital, Yantai, Shandong Province, China; 3Department of Endocrine and Metabolic Diseases, the Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China; 4Emergency Department, the Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
  • Online:2022-04-15 Published:2021-10-18
  • Contact: Peng Sun, MD, PhD, pqhhu25@163.com.

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摘要：

长链非编码RNA HOTTIP具有抗炎作用，且可抑制氧糖导致的神经元凋亡，但其在帕金森病的作用尚待研究。（1）实验以1-甲基-4-苯基吡啶和1-甲基-4-苯基-1,2,3,6-四氢吡啶诱导建立SH-SY5Y和BV2细胞以及C57BL/6雄性小鼠帕金森病体外和体内模型。（2）在细胞学的体外模型中，转染sh-HOTTIP抑制HOTTIP表达后可见，过表达HOTTIP和FOXO1可促进SH-SY5Y细胞凋亡，BV2小胶质细胞活化，促炎性细胞因子表达以及核因子κB和NLRP3炎性小体激活；而过表达miR-615-3p则抑制MPP+诱导的神经细胞凋亡和小胶质细胞炎症反应，并减弱HOTTIP和FOXO1上调介导的神经损伤和炎症反应；（3）在体内模型中，下调HOTTIP可减轻帕金森病小鼠的运动神经功能障碍，并减轻黑质中神经元凋亡和小胶质细胞活化；（4）结果提示抑制HOTTIP可通过调节miR-615-3p/FOXO1抑制帕金森病模型神经元凋亡和小胶质细胞活化。实验于2018年6月经青岛大学附属医院伦理委员会批准（批准号UDX-2018-042）。

https://orcid.org/0000-0001-8902-6925 (Peng Sun)

关键词: 帕金森病, HOTTIP, 非编码RNA, 炎症, miR-615-3p, 细胞凋亡, NLRP3, 神经元

Abstract: HOXA transcript at the distal tip (HOTTIP), a newly identified long noncoding RNA, has been shown to exhibit anti-inflammatory effects and inhibit oxygen-glucose deprivation-induced neuronal apoptosis. However, its role in Parkinson’s disease (PD) remains unclear. 1-Methyl-4-phenylpyridium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were used to establish PD models in SH-SY5Y and BV2 cells and in C57BL/6 male mice, respectively. In vitro, after HOTTIP knockdown by sh-HOTTIP transfection, HOTTIP and FOXO1 overexpression promoted SH-SY5Y apoptosis, BV2 microglial activation, proinflammatory cytokine expression, and nuclear factor kappa-B and NACHT, LRR and PYD domains-containing protein 3 inflammasome activation. Overexpression of miR-615-3p inhibited MPP+-induced neuronal apoptosis and microglial inflammation and ameliorated HOTTIP- and FOXO1-mediated nerve injury and inflammation. In vivo, HOTTIP knockdown alleviated motor dysfunction in PD mice and reduced neuronal apoptosis and microglial activation in the substantia nigra. These findings suggest that inhibition of HOTTIP mitigates neuronal apoptosis and microglial activation in PD models by modulating miR-615-3p/FOXO1. This study was approved by the Ethics Review Committee of the Affiliated Hospital of Qingdao University, China (approval No. UDX-2018-042) in June 2018. 

Key words: apoptosis, inflammation, miR-615-3p, neuron, NLRP3, noncoding RNA, Parkinson’s disease, HOTTIP

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